Study: Rat Fat Drug Offers Human Hope

W A S H I N G T O N, Feb. 6, 2001 -- An injected drug that causes muscles to burn

fat at a high rate may offer hope for controlling extreme obesity,

new U.S. and French laboratory studies suggest.

The study, appearing today in the Proceedings of the NationalAcademy of Sciences, showed that obese mice lost weight despitebeing fed unlimited amounts of food from a diet heavily laced withcalories and fat, said researcher Harvey F. Lodish.

Lodish, a scientist at the Whitehead Institute for BiomedicalResearch and a professor at Massachusetts Institute of Technology,said that even though the drug had a dramatic effect on fat mice,"we have no idea whether it will work in humans."

"Much more research is needed to determine whether thissubstance can be used in humans as an aid in weight loss," hesaid.

The drug is actually part of a protein that Lodish discoveredfive years ago. Called Acrp30, the protein is normally secreted byhuman fat cells. Lodish said that the whole protein apparently hasno effect when injected in mice, but a fragment of the protein,called gAcrp30, does cause weight loss.

Since the drug is a protein, it could not, in its present form,be given as a pill, he said, but would have to be injected.Proteins taken by mouth are usually destroyed during digestion.

Forced Fatty Acid to Burn

Lodish said the drug appears to work by forcing muscles to burnfatty acids at a high rate. Fatty acids are absorbed from food andcan be converted by the body into fat cells.

Since gAcrp30 causes muscles to burn fatty acids extracted fromthe blood stream, the nutrients cannot be turned into fat cells, hesaid.

The drug was tested on laboratory mice that had been fed whatscientists call a "cafeteria diet." This means that the animalswere given unlimited access to food that was high in sugar, butterand oils. The mice quickly became obese, gaining up to twice theweight of mice on a normal diet.

Some of the mice then received daily shots of gAcrp30, whileothers got placebo shots. Both groups of mice continued thecafeteria diet.

After two weeks, the mice getting the drug had lost about 8percent of their weight, said Lodish. Some of these mice, he said,lost one percent of their mass per day, a weight loss rate thatwould not be considered healthy in humans.

The placebo mice did not lose weight, he said.

Other researchers have found compounds for weight control, butthose all worked differently in the body, said Lodish. Leptin, acandidate weight control drug, suppresses appetite by alteringbrain function. Some weight control compounds act by blockingabsorption in the gut of fatty acids, or by inhibiting themetabolism of fatty acids. In those cases, the fat is thenexcreted.

Although gAcrp30 shows promise, Lodish cautioned that extensivetests are needed to determine if the compound has a long-term,detrimental effect on muscle or other tissue.

Dr. Bernard E. Bihain, a vice president of GENSET, a Frenchpharmaceutical research company that holds a patent on gAcrp30,said that his researchers have found that 30 to 40 percent ofextremely obese humans lack the normal levels of gAcrp30,suggesting that this may be a reason for their abnormal weightgain.

Injections of gAcrp30 to control weight, "means that you wouldbe replacing something that is missing" in these obese people,said Bihain, a co-author of the study. "It would be like givinginsulin shots to diabetics," said Bihain.

The GENSET researcher said his firm is conducting extensivesafety tests with gAcrp30. If those tests are successful, the drugcould be tested in Europe by the end of 2001, he said.

"So far we have not seen anything in mice that would be ofconcern," said Bihain. "We have seen no red flag and we havelooked hard."

Bihain cautioned, however, that the drug would appropriate onlyfor extremely obese humans — people who are hundreds of poundsoverweight and who have not responded to other weight controlmeasures.

"This [the drug] is not a toy," said Bihain. "You would useit only in people with life-threatening morbid obesity."